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Title: Projects in Knowledge How to Create a Powerpoint Webcast


1
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2
Social Media, Physicians, and Patients with
Multiple Sclerosis A Guide for the Perplexed
Andrew N. Wilner, MD, FACP, FAAN Neurohospitalist
Department of Neurology Lawrence and Memorial
Hospital New London, Connecticut
3
Please Answer the Following Questions
  • Are you LinkedIn?
  • Did you Friend anyone today?
  • Have you posted questions for your fellow
    Sermoans?
  • Did you tweet this week?

4
Did You Answer Yes?
  • If you answered Yes to all 4 questions, you can
    skip this presentationif not, please continue

5
Social Media
  • The use of web-based technology to facilitate
    interaction with others.

6
What Is Social Media?
  • Media for social interaction, using highly
    accessible and scalable publishing techniques.
    Social media uses web-based technologies to turn
    communication into interactive dialoguesa
    blending of technology and social interaction for
    the co-creation of value. Wikipedia

Wikipedia, The Free Encyclopedia. Social media.
Available at http//en.wikipedia.org/wiki/Social_
media.
7
Social MediaA Few Examples
  • Blogs
  • Facebook, MySpace
  • LinkedIn
  • Sermo
  • Twitter
  • Wikis
  • YouTube
  • Flickr, SmugMug

8
With permission from Solis B, et al. The
conversation prism. Available at
http//www.theconversationprism.com.
9
Nicholas KristofNew York Times Columnist,
February 2010
  • I really think that social media is part of
    the way that we are going to need to continue to
    engage audiences, and I can engage dead white men
    in my column and then I can engage teenyboppers
    with my Facebook pageWe need to try to evolve,
    so thats one reason why I do shoot these videos
    for the New York Times website, why I blog,
    why I Twitter, why I Facebook, why I have a
    YouTube channel.

Williams A. Nicholas Kristof newspaper
columnist, globehopping dinosaur. Time Out New
York. February 18-24, 2010. Available at
http//newyork.timeout.com/articles/i-new-york/828
60/nicholas-kristof-bold-questions.
10
Evolution of Health Information Sharing
  • Used to be 1-way (physician control)
  • Now interactive
  • Physician-patient
  • Patient-physician
  • Patients-patient

11
How Health Information Was Shared
MD
Patient
Slide courtesy of Dr. Bryan Vartabedian.
12
How Health Information Is Shared
MD
ePatient
13
How Health Information Is Shared
ePatients
ePatient
14
Patient Blog on MSLooks Official
Learning to live with multiple sclerosis.
Available at http//learningtolivewithms.blogspot
.com/.
15
The Social Media Revolution How Is Its Use in
Adults Growing?
2005
2009
Lenhart A. Adult and social network websites.
January 14, 2009. Pew Internet American Life
Project. Available at http//pewinternet.org/Rep
orts/2009/Adults-and-Social-Network-Websites.aspx.

16
Percentage of Adults Who Look Online for Health
Information
61
Fox S. The social life of health information.
January 14, 2009. Pew Internet American Life
Project. Available at http//pewinternet.org//m
edia//Files/Reports/2009/PIP_Health_2009.pdf.
17
Health Information Sharing
  • The scale of health information sharing has
    evolved from the doctor, patient, family, and
    friends to MILLIONS OF PEOPLE IN THE WORLD

18
If Social Media Is a Fad, Its a BIG One!
  • Facebook500 million users1
  • Twitter165 million users (90 million
    tweets/day)2
  • LinkedIn80 million users3

1. Facebook. Press room people on Facebook.
Available at http//www.facebook.com/press/info.p
hp?statistics. 2. Twitter blog. newtwitterceo.
October 4, 2010. Available at http//blog.twitter
.com/2010/10/newtwitterceo.html. 3. LinkedIn.
Available at http//www.linkedin.com/.
19
Patient with MS Communicates to the WORLD on
YouTube
Multiple sclerosis CCSVI liberation procedure
NEWS. RADIO SHOW. THE END OF MS. Available at
http//www.youtube.com/watch?v_z8qJrH7VMU.
20
TwitterThe News in 140 Characters!
Multiple sclerosis news and information on
multiple sclerosis (MS). Available at
http//multiplesclerosis.comxa.com/.
21
MS Patient on CCSVI
Abbreviation CCSVI, chronic cerebrospinal venous
insufficiency. Wheelchair kamikaze the rants,
ruminations, and reflections of a mad MS patient.
Available at http//www.wheelchairkamikaze.com/.

22
MS Society Communicates Through News Media
MS Society comments on CCSVI announcement live on
Sky News. Available at http//www.youtube.com/wa
tch?v46Siaot1HL4.
23
American Academy of Neurology Public Webinar on
CCSVI
  • 50 journalists on-site
  • 4000 public attendees online who submitted gt700
    questions
  • http//www.youtube.com/watch?vW2niOdMGsJg

Abbreviation CCSVI, chronic cerebrospinal venous
insufficiency. American Academy of Neurology
National MS Society. CCSVI Web Forum Part 1 of
14. April 2010. Available at http//www.youtube.
com/watch?vW2niOdMGsJg.
24
US Hospitals on YouTube and Twitter
Bennett E. Hospital social network data and
charts. Available at http//ebennett.org/hsnl/dat
a/.
25
How Will Social Media Impact My Patient Care?
  • Positives
  • Patients will find more information
  • Patients will share information with each other
  • Negatives
  • Patients will find more misinformation
  • Patients will share more misinformation with each
    other

26
Where Are the Doctors? MDs in Social Media Space
  • Late adopters
  • Time/impatience
  • Concerns over privacy, liability, and image
  • Physician usage of social media had grown 50 in
    the previous year, according to a June 2009
    survey1

1. Massachusetts Medical Society. Social
networking 101 for physicians. Available at
http//www.massmed.org/Content/NavigationMenu2/Con
tinuingEducationEvents/NewCourses/SocialNetworking
101forPhysicians/ManagingTheRisksOfFacebookTwitter
AndOtherSocialMedia/Managing_The_Risks_O.htm.
27
Advantages of Social Media
  • Wider audience
  • Low cost
  • Instantaneous communication
  • Easy updating
  • InteractiveWeb 2.0
  • Self-education

28
4 Individuals email lists
3 Closed networks MySpace, Facebook
2 Open networks blogs, feeds, YouTube
1 Mainstream media press, influencers
Armano D. Influence ripples. Available at
http//darmano.typepad.com.
29
How You Can Use Social Media to Improve Your
Practice
  • Patient education
  • Promote your practice
  • Recruit patients for clinical trials
  • Cultivate professional relationships

30
Put a stake in the ground
Slide courtesy of Dr. Bryan Vartabedian.
31
Do Physicians Have an Obligation to Be in the
Online Space?
KevinMD.com. Available at http//www.kevinmd.com/
blog/2009/08/delayed-vaccine-schedule-dangerous.ht
ml.
32
  • Visit This Blog's Front Page
  • Neuro Notes
  • Zamboni "Venous Insufficiency" Theory of Multiple
    Sclerosis-Red Flags Warn of Thin Ice
  • Andrew Wilner, MD, Neurology, 1128PM Apr 14,
    2010
  • Here in Canada, ice hockey is big sport. But
    everyone knows you don't go skating on the pond
    when the ice is thin. At the request of the
    National Multiple Sclerosis (MS) Society, the AAN
    hosted a prime time press conference to create a
    venue where the controversial theory that
    "chronic cerebrospinal venous insufficiency"
    (CCSVI) is the etiology of MS could be discussed
    by its leading proponent, Paolo Zamboni, MD,
    Director, Vascular Diseases Center, University of
    Ferrara, Italy, Robert Zivadinov, MD, PhD,
    Director of the Buffalo Neuroimaging Analysis
    Center, Buffalo, NY, Andrew Common, MD,
    Radiologist in Chief, St. Michaels Hospital,
    University of Toronto, Ontario, CA, and Aaron
    Miller, MD, Professor of Neurology and Director
    of the MS Center at Mount Sinai, NY, NY, and
    Chief Medical Officer of the National MS Society.

Medscape Blogs. Neuro Notes. Zamboni "venous
insufficiency" theory of multiple sclerosis-red
flags warn of thin ice. Available at
http//boards.medscape.com/forums?128_at_659.e8Mxapbr
ysT_at_.29fccf6a!comment1.
33
Slide courtesy of Dr. Bryan Vartabedian.
34
Opportunities for Self-Education
  • MedPage Today
  • Medscape
  • Sermo
  • Twitter
  • YouTube

35
Physician Education
Projects In Knowledge. Multiple sclerosis tool
kit diagnosing and understanding cognitive
dysfunction. Available at http//www.projectsinkn
owledge.com/neurology/multiple-sclerosis_1.cfm?jn
2008.
36
Disadvantages of Social Media
  • Information chaos!
  • Misinformation abounds
  • Communication too easy-just a click
  • Lack of patient/physician boundaries
  • Private information becomes public

37
Do Not Practice Medicine!
  • New communication technologies must never
    replace the crucial interpersonal contacts that
    are the very basis of the patient-physician
    relationship. AMA Guidelines for
    Physician-Patient Electronic Communications

American Medical Association. Guidelines for
physician-patient electronic communications.
Available at http//www.ama-assn.org/ama/pub/abou
t-ama/our-people/member-groups-sections/young-phys
icians-section/advocacy-resources/guidelines-physi
cian-patient-electronic-communications.shtml.
38
Staying Safe on Social Networks
  • Never discuss patients by name
  • Do not communicate with patients regarding
    clinical care
  • Block patients from personal Facebook pages
  • Patients, boss, future employer, in-laws, will
    read everything you write
  • Be niceavoid negative comments about your
    hospital, colleagues, and patients!
  • Dont be anonymoustake responsibility for your
    words

39
Just Like a Tattoo
Available at http//www.tattoo-designs-free.com/h
eart.html.
40
It Seemed Like a Good Idea at the Time
  • Everything you write on the internet is engraved
    in stone in the internet cloud
  • Dont say anything you wouldnt want to read in
    the newspaper
  • Self-censorship is a good thing
  • Take a time out before you hit SHARE or
    SEND! (Pause before you post)

41
Dos and Donts of Social Media
  • Educate patients
  • Educate yourself
  • Promote awareness (advertise)
  • Build relationships
  • Be polite
  • Do NOT practice medicine
  • Do NOT socialize with patientsrespect
    boundaries!
  • Never discuss patients by nameHIPAA1
  • Dont say anything online you might regret later

1. Health Insurance Portability and
Accountability Act, 1996. Available at
http//www.cms.gov/HIPAAGenInfo/02_TheHIPAALawandR
elated20Information.aspTopOfPage.
42
Answers to the 4 Questions
  • Are You LinkedIn?business
  • Did you Friend anyone today? Facebook
  • Have you posted questions for your fellow
    Sermoans?clinicians
  • Did you tweet this week?Twitter

43
Learn More About Social Media
  • Social Networking 101 for PhysiciansMassachusetts
    Medical Society CME Program1
  • Guidelines for Physician-Patient Electronic
    CommunicationsAMA2

1. Massachusetts Medical Society CME Program.
Available at http//www.massmed.org/AM/Template.c
fm?sectionCommunication4Template/CM/HTMLDisplay
.cfmContentID32899. 2. American Medical
Association. Available at http//www.ama-assn.org
/ama/pub/about-ama/our-people/member-groups-sectio
ns/young-physicians-section/advocacy-resources/gui
delines-physician-patient-electronic-communication
s.shtml.
44
Thanks for Listening!
  • The End

45
Using Current Treatments to Optimize Patient
Outcomes
  • Jack N. Ratchford, MD
  • Assistant Professor of Neurology
  • Johns Hopkins University School of Medicine
  • Baltimore, Maryland

46
Topics
  • Current disease-modifying treatment options
  • Head-to-head clinical trials
  • High-risk clinically isolated syndrome treatment
    trials
  • Managing breakthrough disease
  • Individualizing MS care
  • Technology for MS patients and clinicians

47
FDA-approved Disease-Modifying MS Treatments
Abbreviations IFN, interferon IM,
intramuscular IV, intravenous PO, by mouth SC,
subcutaneous. Bayer Healthcare Pharmaceuticals
Inc., Montville, NJ Novartis Pharmaceuticals
Corporation, East Hanover, NJ Biogen Idec Inc.,
Cambridge, MA EMD Serono, Inc., Rockland, MA
TEVA Neuroscience, Inc, Kansas City,
MO. Drugs_at_FDA. Available at http//www.accessdata
.fda.gov/Scripts/cder/DrugsatFDA/. Graphic
courtesy of Dr. Jack Ratchford.
48
Recent Head-to-head Trials
  • REGARD1
  • BEYOND2
  • BECOME3
  • TRANSFORMS4

Abbreviations BECOME, Betaferon vs Copaxone in
MS with Triple-Dose Gadolinium and 3-Tesla MRI
Endpoints BEYOND, Betaferon/Betaseron Efficacy
Yielding Outcomes of a New Dose REGARD, Rebif vs
Glatiramer Acetate in Relapsing MS Disease
TRANSFORMS, TRial Assessing injectable InterferoN
vS FTY720 Oral in RrMS. 1. Mikol DD, et al.
Lancet Neurol. 20087903-914. 2. O'Connor P, et
al. Lancet Neurol. 20098889-897. 3. Cadavid D,
et al. Neurology. 2009721976-1983. 4. Cohen JA,
et al. N Engl J Med. 2010362402-415.
49
REGARD
  • Patients relapsing-remitting MS IFNß and
    glatiramer acetate treatment naive
  • Design 96-week, randomized, open-label, SC IFN
    ß-1a vs glatiramer acetate
  • Outcome time to 1st relapse, MRI
  • Results
  • No significant difference in time to 1st relapse
  • No difference in number or change in volume for
    T2 lesions
  • Fewer gadolinium-enhancing lesions in the SC IFN
    ß-1a group
  • Comments similar efficacy less activity than
    expected in the study population

Mikol DD, et al. Lancet Neurol. 20087903-914.
50
BEYOND
  • Patients early, treatment-naive
    relapsing-remitting MS
  • Design randomized to SC IFN ß-1b 500 mcg (higher
    dose), 250 mcg (standard dose), or glatiramer
    acetate
  • Outcome relapse rate, disability progression
  • Results no differences
  • Comments same efficacy for glatiramer acetate,
    SC IFN ß-1b, and double-dose SC IFN ß-1b implies
    a ceiling effect with IFN ß

O'Connor P, et al. Lancet Neurol. 20098889-897.
51
BECOME
  • Patients relapsing-remitting MS or high-risk
    clinically isolated syndrome treatment naive
  • Design SC IFN ß-1b vs glatiramer acetate with
    monthly 3 Tesla MRI using triple-dose gadolinium
  • Outcome number of new or enhancing MRI lesions
  • Result no difference in MRI or clinical activity
  • Comment more evidence of similar efficacy

Cadavid D, et al. Neurology. 2009721976-1983.
52
TRANSFORMS
  • Patients relapsing-remitting MS treatment naive
    or treatment experienced
  • Design 1 year, double blind, fingolimod vs IM
    IFN ß-1a
  • Outcome relapse rate, MRI, disability
  • Results lower relapse rate for fingolimod,
    better MRI results, no effect on disability
  • 2 deaths with high-dose fingolimod (disseminated
    varicella zoster virus and herpes simplex virus
    encephalitis), other adverse events include liver
    function test abnormalities, first dose
    bradycardia/atrioventricular block, macular
    edema, infections, etc

Cohen JA, et al. N Engl J Med. 2010362402-415.
53
Fingolimod
  • First FDA-approved oral disease-modifying MS
    medication
  • Reduced relapse rate, development of new MRI
    lesions, and disability accrual in trials1,2

1. Cohen JA, et al. N Engl J Med.
2010362402-415. 2. Kappos L, et al. N Engl J
Med. 2010362387-401.
54
Fingolimod
  • Potential side effects
  • Increased risk of lower respiratory infections,
    possible increased risk of serious herpes simplex
    virus or varicella zoster virus infections
  • First dose bradycardia or arrhythmia
  • Liver function test elevations
  • Macular edema
  • Dyspnea, drop in diffusion capacity
  • Elevated blood pressure

Cohen JA, et al. N Engl J Med. 2010362402-415.
Kappos L, et al. N Engl J Med. 2010362387-401.
Gilenya PI. East Hanover, NJ Novartis
Pharmaceuticals Corporation 2010.
55
Fingolimod
  • Which patients should be considered for its use?
  • Probably as effective or more effective than
    current first-line treatments, but risks appear
    to be higher
  • Approved as a first-line treatment,1 but best use
    may be patients with active MS who fail an
    injectable treatment or who cannot tolerate
    injectable medications

1. Gilenya PI. East Hanover, NJ Novartis
Pharmaceuticals Corporation 2010.
56
Disease-Modifying Treatment in High-Risk
Clinically Isolated Syndrome
1. Jacobs LD, et al. N Engl J Med.
2000343898-904. 2. Kinkel RP, et al. Neurology.
200666678-684. 3. Comi G, et al. Lancet.
20013571576-1582. 4. Kappos L, et al.
Neurology. 2006671242-1249. 5. Kappos L, et al.
Lancet. 2007370389-397. 6. Comi G et al.
Lancet. 20093741503-1511. Graphic courtesy of
Dr. Jack Ratchford.
57
Managing Breakthrough Disease
  • Challenges of defining breakthrough
  • Options
  • Switch to a different injectable medication
  • Change to natalizumab or fingolimod
  • Add or substitute an off-label treatment (eg,
    pulse steroids, oral immunosuppressants,
    cyclophosphamide, rituximab)
  • Clinical trial

58
Individualizing MS Care
  • 1 approach may not work for everybody
  • Recognizing bad prognostic signs1-3
  • Patients with cerebellar signs or corticospinal
    tract signs at onset
  • Polysymptomatic onset
  • Frequent relapses
  • Poor recovery from relapses
  • African American
  • Male
  • Brain atrophy or many T1 hypointensities on MRI
  • Progressive onset

1. Langer-Gould A, et al. Arch Neurol.
2006631686-1691. 2. Kister I, et al. Neurology.
201075217-223. 3. Bakshi R, et al. Arch
Neurol. 2008651449-1453.
59
Individualizing MS Care Rethinking Current
Treatments
  • Threshold for escalating treatment should be
    lower in patients who are doing poorly
  • Consider agents with different modes of action
  • Induction therapy with mitoxantrone or cytotoxic
    agents followed by maintenance therapy with an
    immunomodulatory agent
  • Biomarkers may be useful to detect patients in
    need of more aggressive early treatment

60
Mitoxantrone Induction Therapy
  • Case series of 100 patients1
  • Patients aggressive relapsing-remitting MS
    (RRMS) treatment naive or treatment experienced
  • Design monthly mitoxantrone (20 mg) and
    methylprednisolone (1 g) for 6 months
  • 73 patients received maintenance therapy within 6
    months following induction mitoxantrone q3mo (n
    21), IFN-ß (n 25), azathioprine (n 15),
    methotrexate (n 7), or glatiramer acetate (n
    5)
  • Trial of glatiramer acetate maintenance after
    mitoxantrone induction vs galtiramer acetate
    alone2,3
  • Patients RRMS
  • Design 12 months glatiramer acetate (20 mg/d)
    following 3 monthly mitoxantrone infusions (12
    mg/m2) or 15 months glatiramer acetate alone (20
    mg/d)

1. Le Page E, et al. J Neurol Neurosurg
Pyschiatry. 20087952-56. 2. Vollmer T, et al.
Mult Scler. 200814663-670. 3. Arnold DL, et al.
J Neurol. 20082551473-1478.
61
Other Induction Therapies
  • High-dose cyclophosphamide induction1
  • Patients aggressive relapsing-remitting MS
    (RRMS) treatment naive or treatment experienced
  • Design 2-year open-label trial in 9 patients
    high-dose cyclophosphamide (50 mg/kg/d IV) for 4
    consecutive days, followed by granulocyte
    colony-stimulating factor (filgrastim)
  • Autologous stem cell transplantation2
  • Patients RRMS treatment experienced
  • Design phase I/II study
  • Peripheral blood hematopoietic stem cells
    mobilized with cyclophosphamide (2 g/m2 IV)
    followed by filgrastim
  • Mobilized cells collected by apheresis
  • Conditioning regimen cyclophosphamide (200 mg/kg
    IV) in 4 equal fractions plus alemtuzumab or
    rabbit antithymocyte globulin
  • Cells reinfused 36 hours after completion of
    cyclophosphamide

1. Krishnan C, et al. Arch Neurol.
2008651044-1051. 2. Burt RK, et al. Lancet
Neurol. 20098244-253.
62
Technology for MS Patients
  • Many MS patients are savvy internet users
  • Increasingly, patients are using social media to
    get information about their MS and communicate
    with peers
  • gt20,000 MS patients use PatientsLikeMe1
    (www.patientslikeme.com)
  • MS World is the official chat service and
    bulletin board for the National MS Society2
    (www.msworld.org)

1. The PatientsLikeMe Multiple Sclerosis
Community. Available at http//www.patientslikeme
.com/multiple-sclerosis/community. 2.
MSWorld.org. Available at http//www.msworld.org/
.
63
Technology for MS Patients
  • Online symptom surveys for patients
  • Can be used to screen for problems and be shared
    with a healthcare professional
  • https//www.mymshealth.org

My MS Health. Available at https//www.mymshealth
.org/.
64
Technology for MS Clinicians
  • Clinical prediction tool
  • Gives predictions of relapse rate, Expanded
    Disability Status Scale, and time to progression
    for the subsequent 2 years based on individual
    characteristics1
  • https//www.slcmsr.net/public/login.jsp
  • iPoint of Care-MS
  • A widget on a desktop computer or iPhone that
    allows one to quickly search for relevant
    resources2
  • http//ms.ipointofcare.org/Default.aspx

1. Daumer M, et al. BMC Med Inform Decis Mak.
2007711. 2. Multiple Sclerosis. iPointOfCare.
Available at http//ms.ipointofcare.org/Therapeut
icAreas.aspx?ctrlFAQstypeMS.
65
Technology for MS Clinicians
  • Resource Detectives
  • An online tool to find local resources for
    patients (eg, physical therapy, legal advice,
    clinical trials)
  • www.resourcedetectives.org
  • Consortium of MS Centers website
  • Consensus guidelines and other resources
  • www.mscare.org
  • National MS Society website
  • Many resources for MS clinical care and research
  • www.nationalmssociety.org

66
Future Directions in MS Therapy Are Neurologists
Becoming Immunologists Online?
  • Augusto A. Miravalle, MD
  • Assistant Professor of Neurology
  • University of Colorado, Denver
  • Aurora, Colorado

67
Overview
  • Understand basic mechanisms of action underlying
    selected current and experimental therapies for
    MS
  • Review efficacy and safety data on emerging MS
    therapies
  • Understand potential risk and benefits of social
    media and technology in the care of MS patients

68
Definitions
  • Immunosuppressive therapies
  • Cause generalized immune suppression
  • Limited therapeutic potential due to systemic
    effects
  • Immunomodulatory therapies
  • Do not cause generalized immune suppression
  • Shift the immune response from proinflammatory
    (Th1) to more beneficial anti-inflammatory (Th2)
    response
  • Protective/repair therapies
  • Desirable to support neural regeneration and
    inhibit neural degeneration
  • Effective strategy in MS, as disease is diagnosed
    early, before the brain has sustained lasting
    damage

69
Treatment Algorithms for MS
  • Treatment for MS can follow 1 of 2 principal
  • algorithms
  • Induction algorithms concentrate all therapeutic
    efforts on the early phases of the disease, which
    ultimately defines prognosis
  • Escalation algorithms begin with the safest
    treatments and move on to more aggressive
    therapies only in the event of treatment failure

70
Treatments for MS
  • Current first-line treatments for MS are
    typically monotherapies, but disease activity is
    insufficiently controlled by these treatments in
    some patients
  • Second-line monotherapies are limited and
    associated with greater safety concerns
  • Alternatively, combination therapy with
    established drugs can improve clinical efficacy
    while managing the potential for adverse events

71
  • Who are the candidates for emerging therapies?
  • Will emerging therapies be used as part of
    combination therapy?

72
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
73
Fingolimod Mechanism of Action
  • Fingolimod targets receptors for sphingosine
    1-phosphate (S1P), a signaling lipid released at
    sites of inflammation
  • S1P receptors are found on the surface of newly
    generated T-cells and promote T-cell migration
    from lymphatic organs to peripheral sites of
    inflammation
  • T-cells that have fingolimod bound to receptors
    do NOT egress
  • Fingolimod is lipid-soluble and readily permeates
    the blood brain barrier to enter the central
    nervous system

Rammohan KW, et al. Neurology. 201074S47-S53.
74
Fingolimod Mechanism of Action
Abbreviations CNS, central nervous system LN,
lymph node S1P, sphingosine 1-phosphate. Rammohan
KW, et al. Neurology. 201074S47-S53. Graphic
courtesy of Dr. Augusto Miravalle.
75
Fingolimod Clinical Experience
  • Phase II trial in relapsing-remitting MS
    patients1
  • Doses 1.25 and 5 mg
  • Significantly reduced the number of new focal
    inflammatory lesions (by 80) and relapse rates
    (by 50) compared with placebo
  • Phase III trial (TRANSFORMS)2
  • 12 months
  • Doses 0.5 and 1.25 mg
  • Comparing fingolimod with once-weekly IFN ?-1a
  • Significant reduction of relapse rate and MRI
    activity
  • 2 fatalities related to varicella zoster virus
    and herpes simplex virus encephalitis infections

1. Kappos L, et al. N Engl J Med.
20063551124-1140. 2. Cohen JK, et al. N Engl J
Med. 2010362402-415.
76
Fingolimod Clinical Experience
  • Phase III trial (FREEDOMS)
  • 24 months
  • Doses 0.5 and 1.25 mg
  • Reduced annualized relapse rates by 54 and 60,
    respectively
  • Reduced accumulation of disability on both doses
  • 30 reduction in the rate of brain volume loss at
    6 months of therapy

Kappos L, et al. N Engl J Med. 2010362387-401.
77
Fingolimod Safety and Pharmacokinetics
  • Safety
  • Potential adverse effects (as observed in phase
    II and III clinical trials for MS) include1-3
  • Pharmacokinetics
  • Serum half-life is 7 days4
  • Reduces peripheral lymphocyte counts for up to 24
    hours following administration4

1. Kappos L, et al. N Engl J Med.
20063551124-1140. 2. Cohen JK, et al. N Engl J
Med. 2010362402-415. 3. Kappos L, et al. N Engl
J Med. 2010362387-401. 4. Brown BA, et al. Ann
Pharmacother. 2007411660-1668.
78
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
79
Cladribine Mechanism of Action
  • Cladribine exploits the specific enzymatic
    degradation of deoxynucleotides in lymphocytes
  • Most cells do not rely on adenosine deaminase
    (ADA) to degrade deoxyadenosine phosphate,
    because of high levels of deoxynucleotidase
    (5?-NTase), a dephosphorylating enzyme
  • Lymphocytes do rely on ADA to degrade
    deoxyadenosine phosphate, because of low levels
    of 5?-NTase
  • Since cladribine is resistant to ADA, and
    lymphocytes have low levels of 5?-NTase,
    cladribine results in the accumulation of
    deoxyadenosine nucleotides in lymphocytes

Leustatin PI. Raritan, NJ Ortho Biotech
Products, LP 2007.
80
Cladribine Clinical Experience
  • Phase III trial (CLARITY)1
  • In patients with relapsing-remitting MS
  • Compared with placebo, significant reduction in
  • Relapse rate (by 5558)
  • Disability progression (by 3133)
  • Number of gadolinium-enhancing active T2 lesions
    (by 7388)
  • Phase III trial (ORACLE MS)2
  • In patients with clinically isolated syndrome
  • Currently under way

1. Giovannoni G, et al. N Engl J Med.
2010362416-426 2. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/s
how/NCT00725985.
81
Cladribine Safety and Pharmacokinetics
  • Safety
  • Infection is the chief safety concern1
  • In clinical trials, adverse events included2
  • Pharmacokinetics
  • Serum half-life of 68 hours3
  • Immunosuppression maintained for at least 612
    months3

1. Cohen JA. Arch Neurol. 200966821-828. 2.
Giovannoni G, et al. N Engl J Med.
2010362416-426. 3. Leist TP, et al. Curr Med
Res Opin. 2007232667-2676.
82
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
83
Teriflunomide Mechanism of Action
  • An inhibitor of the mitochondrial dihydroorotate
    dehydrogenase (DHODH), an enzyme crucial to
    pyrimidine synthesis
  • Activated lymphocytes depend on de novo
    pyrimidine synthesis
  • Depletion could
  • Inhibit immune-cell proliferation
  • Impair phospholipid synthesis and protein
    glycosylation in immune cells

Reprinted from Tallantyre E, et al. The
International MS Journal. 20081562-68 with
permission from Cambridge Medical Publications
(CMP).
84
Teriflunomide Clinical Experience
  • Phase II trial1
  • Patients with relapsing forms of MS
  • Received placebo, teriflunomide 7 mg or 14 mg a
    day for 36 weeks
  • Significant reduction in the number of T1- and
    T2-enhancing lesions vs placebo
  • Phase II trials of combination therapy with IFN-?
    and with glatiramer acetate are currently under
    way2-4

1. O'Connor PW, et al. Neurology.
200666894-900. 2. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00475865. 3. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00489489. 4. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00811395.
85
Teriflunomide Clinical Experience
  • Phase III trial (TEMSO)1
  • A 2-year, double-blind, placebo-controlled study
    examining relapse rate in relapsing MS recently
    completed1
  • Other phase III trials in relapsing MS (TOWER,
    TENERE) currently under way2,3
  • Phase III trial (TOPIC)4
  • A 2-year, double-blind placebo-controlled study
    in clinically isolated syndrome currently under
    way

1. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00134563
. 2. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00751881
. 3. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00883337
. 4. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00622700
.
86
Teriflunomide Safety and Pharmacokinetics
  • Safety
  • Adverse effects in clinical trials included1,2
  • Contraindicated in women of childbearing age1,2
  • Pharmacokinetics
  • Mean plasma half-life is 1518 days2

1. Cohen JA. Arch Neurol. 200966821-828. 2.
Tallantyre E, et al. Int MS J. 20081562-68.
87
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
88
Daclizumab Mechanism of Action
  • A humanized monoclonal antibody targeting CD25
    receptors1
  • Inhibits proliferation and activation of T-cells,
    including autoreactive T-cells1
  • Promotes expansion of CD56 natural killer (NK)
    cells mechanism unknown2
  • In clinical trials, expanded CD56 NK cells were
    capable of killing autoreactive CD4 and CD8
    T-cells and were correlated with clinical
    outcome3,4

1. Lutterotti A, et al. Lancet Neurol.
20087538-547. 2. Buttmann M, et al. Expert Rev
Neurother. 20088433-455. 3. Bielekova B, et al.
Arch Neurol. 200966483-489. 4. Bielekova B, et
al. Proc Natl Acad Sci U S A. 20061035941-5946.
89
Daclizumab Clinical Experience
  • Phase II trial (CHOICE)1
  • Investigated daclizumab as an add-on therapy in
    patients with relapsing-remitting MS
  • In the high-dose group, daclizumab produced a
    significant 72 reduction in new or enlarged
    gadolinium-enhancing lesions on MRI scans over a
    6-month period vs placebo
  • No differences in annualized relapse rates
    between the study arms
  • Additional phase II and phase III studies are
    ongoing2-4

1. Wynn D, et al. Lancet Neurol. 20109381-390.
2. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00390221
. 3. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00870740
. 4. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT01064401
.
90
Daclizumab Safety and Pharmacokinetics
  • Safety
  • The most common and serious adverse effects in
    clinical trials were1
  • Cutaneous reactions more frequently observed with
    daclizumab than placebo (44 vs 39)
  • Severe infections more frequently observed with
    daclizumab than placebo (7 vs 3)
  • Pharmacokinetics
  • Serum half-life approximately 20 days2

1. Wynn D, et al. Lancet Neurol. 20109381-390.
2. Buttmann M, et al. Expert Rev Neurother.
20088433-455.
91
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
92
Rituximab Mechanism of Action
  • A chimeric monoclonal antibody targeting CD20
    receptors1
  • Causes selective B-cell destruction1
  • Thought to have a therapeutic effect in MS, where
    localized B-cell expansion in the central nervous
    system is associated with inflammation1

1. Lutterotti A, et al. Lancet Neurol.
20087538-547.
93
Rituximab Clinical Experience
  • Phase II trial (HERMES)1,2
  • Patients with relapsing-remitting MS
  • Resulted in reduction of mean number of
    gadolinium-enhancing lesions (by 91) and relapse
    rate (by 58) vs placebo
  • Phase II/III (OLYMPUS)3
  • Patients with primary-progressive MS
  • Appeared to have efficacy only in young patients
    and those with signs of active inflammation on
    MRI scans
  • Phase I/II (RIVITaLISe)4
  • Patients with secondary-progressive MS
  • Initiated in September 2010
  • 1. Hauser SL, et al. N Engl J Med.
    2008358676-688. 2. Buttmann M, et al. Expert
    Rev Neurother. 20088433-455.
  • 3. Hawker K, et al. Ann Neurol. 200966460-471.
    4. ClinicalTrials.gov. 2010. Available at
    http//www.clinicaltrials.gov/ct2/show/NCT01212094
    .

94
Rituximab Safety and Pharmacokinetics
  • Safety
  • Long-term safety profile has yet to be
    established1
  • 5 cases of progressive multifocal encephalopathy
    reported in patients with rheumatoid arthritis or
    systemic lupus erythematous receiving rituximab
    in conjunction with other immunosuppressants1,2
  • Other adverse events included infusion reactions,
    chills, pruritis, pyrexia, throat irritation,
    urinary tract infections, and sinusitis3,4
  • Pharmacokinetics
  • Flexible or fixed dosing1
  • 375 mg/m² given weekly for 4 weeks
  • 2 grams divided in 2 infusions of 1 gram each, 2
    weeks apart
  • Serum half-life approximately 19 days1
  • Following administration of 2 grams of rituximab,
    CD19-positive B-cells are rapidly depleted and
    remain undetectable for up to 6 months3

1. Buttmann M, et al. Expert Rev Neurother.
20088433-455. 2. FDA. 2009. Available at
http//www.fda.gov/Safety/MedWatch/SafetyInformati
on/SafetyAlertsforHumanMedicalProducts/ucm187791.h
tm. 3. Hauser SL, et al. N Engl J Med.
2008358676-688. 4. Hawker K, et al. Ann Neurol.
200966460-471.
95
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
96
Ocrelizumab
  • Humanized monoclonal antibody targeting CD19
    B-cells.
  • Recent phase II clinical trials using ocrelizumab
    (2000 mg 600 mg) vs placebo showed 96 reduction
    on number of MRI lesions, as well as 80
    reduction on annualized relapse rate
  • Safety profile was limited to infusion-related
    events (43), mild infections, and systemic
    inflammatory response syndrome

Kappos et al. Efficacy and Safety of Ocrelizumab
in Patients with RRMS Results of a Phase II
Randomized Placebo-Controlled Multicenter Trial.
ECTRIMS 2010.
97
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
98
Alemtuzumab Mechanism of Action
  • A humanized monoclonal antibody targeting cells
    expressing CD52 receptors1
  • CD52 is a glycoprotein of unknown function,
    expressed on T- and B-cells, monocytes, and
    eosinophils1
  • Alemtuzumab causes rapid immune cell depletion
    (2 days) mediated by complement-mediated lysis
    and antibody-dependent cellular cytotoxicity2,3
  • Following treatment
  • CD4 T-cells are depleted for 60 months (median)
  • B-cells and monocytes are depleted for 3 months
    (median)

Abbreviation PBMC, peripheral blood mononuclear
cell. 1. Lutterotti A, et al. Lancet Neurol.
20087538-547. 2. Buttmann M, et al. Expert Rev
Neurother. 20088433-455. 3. Cohen JA. Arch
Neurol. 200966821-828.
99
Alemtuzumab Clinical Experience
  • Phase II trial1
  • Patients with relapsing-remitting MS
  • Compared with conventional IFN-ß therapy,
    significant benefit in
  • Disability progression
  • Relapse rate
  • T2 hyperintense lesion volume change
  • Brain volume
  • Phase III trials2,3
  • 2 trials (CARE-MS I, CARE-MS II) for the
    treatment of RRMS currently under way

1. CAMMS223 Trial Investigators. N Engl J Med.
20083591786-1801. 2. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00530348. 3. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00548405.
100
Alemtuzumab Safety and Pharmacokinetics
  • Safety
  • Common and serious adverse events in clinical
    trials included1-3
  • As a result of several cases of ITP, including 1
    fatal case, a patient monitoring program was
    instituted for the remainder of the phase II
    trial1
  • The most serious observed adverse event was
    autoimmunity, with autoimmune thyroid disorders
    affecting 2330 of patients in clinical
    trials1,2
  • Pharmacokinetics
  • Serum half-life of approximately 8 days3
  • Suppressed B-cells and monocytes for 3 months,
    CD4 T-cells for 61 months, and CD8 T-cells for
    30 months following infusion3

1. CAMMS223 Trial Investigators. N Engl J Med.
20083591786-1801. 2. Cohen JA. Arch Neurol.
200966821-828 3. Buttmann M, et al. Exp Rev
Neurother. 20088433-455.
101
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtsey of Dr. Augusto Miravalle.
102
Laquinimod Mechanism of Action
  • An immunomodulator derivative of linomide1
  • Anti-inflammatory properties of laquinimod are
    attributed to
  • Effects on MHC-II gene transcription
  • Stimulation of neurotrophins and neurotrophic
    factor
  • Activation of anti-inflammatory pathways
  • Promotion of apoptosis in CD8 and B-cells
  • Inhibition of CD14 and natural killer cells
  • As a consequence, there is cytokine balance in
    favor of anti-inflammatory Th2/Th3 cytokines,
    with suppression of proinflammatory and cytokine
    related genes2

1. Cohen JA. Arch Neurol. 200966821-828. 2.
Yang JS, et al. J Neuroimmunol. 20041563-9.
103
Laquinimod Clinical Experience
  • Phase II trial1
  • Patients with relapsing-remitting MS (RRMS)
  • Significant decreases in the number of active
    lesions vs placebo
  • No significant difference in relapses or
    disability progression vs placebo
  • Phase IIb trial2
  • Patients with RRMS
  • Daily dose 0.6 mg
  • Significantly reduced MRI disease activity
    (cumulative number of gadolinium-enhancing
    lesions) by 60 vs placebo
  • Phase III trials3,4
  • 2 trials (ALLEGRO, BRAVO) for the treatment of
    RRMS currently under way

1. Polman C, et al. Neurology. 200564987-991.
2. Comi G, et al. Lancet. 20083712085-2092. 3.
ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00509145
. 4. ClinicalTrials.gov. 2010. Available at
http//www.clinicaltrials.gov/ct2/show/NCT00605215
.
104
Laquinimod Safety and Pharmacokinetics
  • Safety
  • Serious adverse events included Budd-Chiari
    syndrome and menometrorrhagia with myofibroma1
  • Other adverse events included arthralgia, eye
    pain, chest pain, menstrual disorders, and mild
    dose-dependent increases in liver enzymes1,2
  • Pharmacokinetics
  • Based on preclinical animal studies, high oral
    bioavailability, and low total clearance rate3

1. Comi G, et al. Lancet. 20083712085-2092. 2.
Polman C, et al. Neurology. 200564987-991. 3.
Preiningerova J. Expert Opin Investig Drugs.
200918985-989.
105
Abbreviations A, astrocytes BBB, blood brain
barrier BDNF, brain-derived neurotrophic factor
IL-4, interleukin 4 MØ, macrophages NT3,
neurotrophin-3 ODC, oligodendrocytes. Graphic
courtesy of Dr. Augusto Miravalle.
106
Dimethyl Fumarate (BG00012) Mechanism of Action
  • Activates nuclear factor E2-related factor 2
    (Nrf2) transcriptional pathway1
  • May also provide a neuroprotective effect by
    inducing phase II detoxification genes2,3
  • Eg, NAD(P)Hquinone oxidoreductase-1 (NQO-1)
  • Abbreviations GSH, glutathione NADPH,
    nicotinamide adenine dinucleotide phosphate
    NF?B, nuclear factor ?B.
  • 1. Cohen JA. Arch Neurol. 200966821-828. 2.
    Rammohan KW, et al. Neurology. 201074S47-S53.
    3. Wierinckx A, et al. J Neuroimmunol. 2005
    266132-143.
  • Graphic courtesy of Dr. Augusto Miravalle.

107
Dimethyl Fumarate (BG00012) Clinical Experience
  • Phase IIb trial1
  • Patients with relapsing-remitting MS
  • Significant reduction of new gadolinium-enhancing
    lesions
  • No significant effect on relapse rate
  • Phase III trials
  • 2 trials (DEFINE, CONFIRM) are currently under
    way2,3

1. Kappos L, et al. Lancet. 2008
253721463-1472. 2. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00420212. 3. ClinicalTrials.gov. 2010.
Available at http//www.clinicaltrials.gov/ct2/sh
ow/NCT00451451.
108
Dimethyl Fumarate (BG00012) Safety and
Pharmacokinetics
  • Safety
  • The most commonly observed adverse effects in
    clinical trials were1
  • Pharmacokinetics
  • Serum half-life of dimethyl fumarate
    approximately 12 minutes2
  • Serum half-life of active metabolite
    approximately 36 hours2
  • Biologic effects are estimated to last even
    longer2

1. Kappos L, et al. Lancet. 2008
253721463-1472. 2. Lee D-H, et al. Int MS J.
20081512-18.
109
Social Media in MS
110
Definition
  • Social media is the integration of social
    interaction, technology, and medicine
  • Some examples of social media include
  • Communication
  • Blogs
  • Social networking
  • Collaboration/education
  • Wikipedia
  • Social bookmarking
  • Ratings

111
Communication
  • Patients-to-patients blogs
  • Benefits
  • Helpful for patients to share and discuss with
    similar communities daily life problems
  • Share symptoms, concerns, and questions on
    treatment options
  • Risks
  • Potential for assuming that shared answers and
    advice are based on scientific evidence
  • Physicians-to-patients blogs
  • Benefits
  • Facilitate access to answers to common questions
  • Risks
  • Use of this method for emergent-urgent
    health-related issues
  • Lack of confidentiality

112
Collaboration/Education
  • Physicians-to-physicians blogs
  • Benefits
  • Rapid access and dissemination of information
    from experts across geographies and specialties
  • Improve practice management
  • Collaborate on difficult case presentations
  • CME
  • Risks
  • Usually no peer-to-peer review and poor editorial
    oversight
  • Networking
  • Benefits
  • Build a referral base or network
  • Expand your interactions
  • Search for colleagues
  • Risks
  • Privacy

113
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